Imidazoylalkyl substituted with a six membered nitrogen containing heterocyclic ring

ABSTRACT

Disclosed is a compound of Formula 1.0: ##STR1## or a pharmaceutically acceptable salt or solvate thereof. Also disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a Compound of Formula 1.0. 
     Further disclosed is a method of treating allergy (for example asthma), inflammation, hypertension, raised intraocular pressure (such as glaucoma)--i.e., a method of lowering intraocular pressure, sleeping disorders, states of hyper and hypo motility and acidic secretion of the gastrointestinal tract, hypo and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimers, Schizophrenia, and migraine) comprising administering an effective amount of a compound of Formula 1.0 to a patient in need of such treatment.

This application is a 371 of PCT/US 92/10698 filed Dec. 16, 1992.

BACKGROUND

H₃ receptor sites are known and are of current interest to those skilledin the art--for example, see: West, Jr. et al., "Biexponential Kineticsof (R)-α- ³ H!Methylhistamine Binding to the Rat Brain H₃ HistamineReceptor", Journal of Neurochemistry, Vol. 55, No. 5, pp. 1612-1616,1990; West, Jr. et al., "Identification of Two H₃ -Histamine ReceptorSubtypes", Molecular Pharmacology, 38:610-613; and Korte et al.,"Characterization and Tissue Distribution of H₃ Histamine Receptors inGuinea Pigs by N.sup.α -Methylhistamine", Biochemical and BiophysicalResearch Communications, Vol. 168, No. 3, pp. 979-986.

Arrang et al. in U.S. Pat. No. 4,767,778 (Issued Aug. 30, 1988) disclosea pharmaceutical composition containing a histamine derivative of theformula: ##STR2## wherein each of R₁, R₂, and R₄, represents a hydrogenor a methyl, or R₁ and R₂ taken together represent a methylene, and R₃is a hydrogen, a methyl or a carboxy, with the proviso that R₁, R₂, R₃,and R₄ are not simultaneously methyl groups. It is disclosed that thederivatives behave as complete agonists of the H₃ receptors in rat brainand produce a maximal inhibition of release identical to that induced byhistamine (approximately 60%). It is also disclosed that the histaminederivatives powerfully inhibit the release and synthesis of histamine byvery selectively stimulating the H₃ receptors. Consequently, accordingto Arrang et al., the derivatives are likely to decrease histaminergictransmission in the digestive tract and in the nervous, cardiovascularand immune systems. Arrang et al. disclose that the derivatives can beused in therapy as a drug having sedative effects, as a sleep regulator,anticonvulsant, regulator of hypothalamo-hypophyseal secretion,antidepressant, and modulator of cerebral circulation. According toArrang et al., inhibition of the release of inflammation messengers invarious allergic conditions (e.g., asthma) is expected to result fromstimulation of the H₃ receptors of the lung. It is further disclosedthat the inhibition of release of gastric histamine is likely to exertantisecretory and antiulcerative effects. According to Arrang et al.,modification of release of the messengers of immune responses is likelyto modulate the latter responses.

EP 0 338 939 discloses compounds of the formula: ##STR3##

Derwent abstract 86-273706(42 for EP 0 197 840 discloses imidazolederivatives of the formula: ##STR4## wherein R₁ is H, methyl or ethyl; Ris H or R₂ ; and R₂ is 1-6C alkyl, piperonyl,3-(benzimidazolon-1-yl)propyl, --CZ--NHR₅ or a group (i): ##STR5##wherein n is 0-3; X is a bond, O, S, NH, CO, CH═CH or a group (ii):##STR6## R₃ is H, methyl, halo, CN, CF₃ or COR₄ ; R₄ is 1-6C alkyl, 3-6Ccycloalkyl or phenyl (optionally substituted by methyl or F); Z is O, S,NH, N-methyl or N--CN; and R₅ is 1-8C alkyl, 3-6C cycloalkyl (optionallysubstituted by phenyl), 3-6C cycloalkyl(1-3C)alkyl, phenyl (optionallysubstituted by methyl, halo or CF₃), phenyl(1-3C)alkyl, naphthyl,adamantyl or p-toluenesulphonyl. It is disclosed that these compoundsare psychotropic agents. It is also disclosed that these compoundsantagonise the histamine H3 receptors and increase the speed of cerebralhistamine renewal.

Derwent abstract 90184730/24 for U.S. Pat. No. 4,925,851 discloses 2- or4-(2-(1H-imidazol-1-yl)ethyl) piperidine compounds useful as antitumouragents for inhibiting lymphoma, sarcoma, myeloma and leukaemia. Thecompounds have the formula: ##STR7## wherein R is --CH₂ (CH₂)_(m) --Me,--CO--(CH₂)_(m) --Me or --CO--CMe₂ --R₂ ; m is 2-18; R₂ is H or Me; R₁is --(CH₂)_(n) --R_(3;) n is 0-13; R₃ is H, i-Pr or t-Bu; and thefloating group is at the 2- or 4- position; with the proviso that (1)the sum of C atoms in R₁ does not exceed 13; and (2) the sum of C atomsin R and R₁ does not exceed 25.

Derwent abstract 90-180087/24 for EP 372125A discloses compounds of theformula: ##STR8## wherein X is O or S; R₁ is halo, CF₃, CN, NO₂, OH, or1-6C alkoxy; R₂ is H, 1-6C alkyl, aryl, 7-13C aralkyl, optionallysubstituted amino or 5- or 6-membered N-containing ring; and R₃ is 1-6Chydrocarbyl, 7-13C aralkyl or 1-13C acyl. It is disclosed that thesecompounds have alpha2-antagonist activity with no dopamine activity andthat they are useful for treating depression and other related illnesses(e.g., anxiety or cognitive disorders).

Derwent abstract 88-309195/44 for U.S. Pat. No. 4,935,417 disclosescompounds of the formula: ##STR9## wherein (according to U.S. Pat. No.4,935,417) R¹ is aryl, lower alkyl, cycloalkyl or hydrogen; R² is aryl,lower alkyl or hydrogen; R³ is lower alkyl, hydroxy or hydrogen; R⁴ isaryl or hydrogen; R⁵ is aryl or hydrogen; m is two or three; n is zero,one or two, provided that when R³ is hydroxy, n is one or two; and q iszero, one, two or three. U.S. Pat. No. 4,935,417 discloses that thesecompounds are calcium channel antagonists useful for treating mammalshaving a variety of disease states, such as stroke, epilipsy,hypertension, angina, migraine, arrhythmia, thrombosis, embolism andalso for treatment of spinal injuries

Compounds known in the art include: ##STR10##

Known compounds in the art also include compounds of the formula:##STR11## wherein R (Table 1) is:

                  TABLE 1                                                         ______________________________________                                        NO.  R                 RN         CA                                          ______________________________________                                        1    --CH.sub.3        106243-44-1                                                                              106(11):84602r                              2    --CH(CH.sub.3).sub.2                                                                            106243-45-2                                                                              106(11):84602r                              3    H                 106243-23-6                                                                              106(11):84602r                              4    --C(S)NHC(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3)                                                  106243-93-0                                                                              106(11):84602r                              5    --C(O)NHCH(CH.sub.3)(phenyl)                                                                    106243-90-7                                                                              --                                          6    --C(S)NH(p-chlorophenyl)                                                                        106243-85-0                                                                              --                                          7    --C(O)NH(phenyl)  106243-77-0                                                                              --                                          8    --C(NH)N(CH.sub.3)(cyclopropyl)                                                                 106243-73-6                                                                              --                                          9    --C(S)NHCH.sub.3  106243-61-2                                                                              --                                          10   --CH.sub.2 CH.sub.2 -phenyl                                                                     106243-49-6                                                                              --                                          11   --CH.sub.2 CH.sub.2 -p-flurophenyl                                                              106243-67-8                                                                              --                                          12   benzyl            106243-25-8                                                                              --                                          ______________________________________                                    

Additionally known compounds include: ##STR12##

In view of the art's interest in compounds which effect the H₃receptors, novel compounds having agonist or antagonist activity on H₃receptors would be a welcome contribution to the art. This inventionprovides just such a contribution by providing novel compounds having H₃agonist or antagonist activity.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula: ##STR13## or apharmaceutically acceptable salt or solvate thereof, wherein: (A) m isan integer selected from the group consisting of: 1 and 2;

(B) n and p are integers and are each independently selected from thegroup consisting of: 0, 1, 2, 3, and 4 such that the sum of n and p is 4and T is a 6-membered ring;

(C) R³ and R⁴ are each independently bound to the same or differentcarbon atom of ring T such that there is only one R³ group and one R⁴group in ring T, and each R¹, R², R³, and R⁴ is independently selectedfrom the group consisting of:

(1) H;

(2) C₁ to C₆ alkyl; and

(3) --(CH₂)_(q) --R⁶ wherein q is an integer of: 1 to 7, and R⁶ isselected from the group consisting of: phenyl, substituted phenyl,--OR⁷, --C(O)OR⁷, --C(O)R⁷, --OC(O)R⁷, --C(O)NR⁷ R⁸, CN and --SR⁷wherein R⁷ and R⁸ are as defined below, and wherein the substituents onsaid substituted phenyl are each independently selected from the groupconsisting of: --OH, --O--(C₁ to C₆)alkyl, halogen, C₁ to C₆ alkyl,--CF₃, --CN, and --NO₂, and wherein said substituted phenyl containsfrom 1 to 3 substituents;

(D) R⁵ is selected from the group consisting of:

(1) H;

(2) C₁ to C₂₀ alkyl;

(3) C₃ to C₆ cycloalkyl;

(4) --C(O)OR^(7') ; wherein R⁷ ' is the same as R⁷ defined below exceptthat R^(7') is not H;

(5) --C(O)R⁷ ;

(6) --C(O)NR⁷ R⁸ ;

(7) allyl;

(8) propargyl; and

(9) --(CH₂)_(q) --R⁶, wherein q and R⁶ are as defined above, and when qis equal to 1, then R⁶ is not OH or SH;

(E) R⁷ and R⁸ are each independently selected from the group consistingof: H, C₁ to C₆ alkyl, and C₃ to C₆ cycloalkyl;

(F) the dotted line (------) represents a double bond that is optionallypresent when m is 1, and n is not 0, and p is not 0 (i.e., the nitrogenin the ring is not bound directly to the carbon atom bearing the doublebond), and when said double bond is present then R² is absent; and

(G) when m is 2, each R¹ is the same or different substituent for eachm, and each R² is the same or different substituent for each m, and atleast two of the substituents R¹ and/or R² are H.

Those skilled in the art will appreciate that the total number ofsubstituents on each of the --(C)_(n) -- and --(C)_(p) -- groups is two,and that such substituents are independently selected from the groupconsisting of hydrogen, R³ and R⁴, such that there is a total of onlyone R³ and one R⁴ substituent in ring T.

This invention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and an effective amount of aCompound of Formula 1.0.

This invention further provides a method of treating allergy, (forexample asthma), inflammation, hypertension, states of hyper and hypomotility and acidic secretion of the gastrointestinal tract, hypo andhyperactivity of the central nervous system (for example, agitation anddepression) and other CNS disorders (such as Alzheimers, Schizophrenia,and migraine) comprising administering an effective amount of a compoundof Formula 1.0 to a patient in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following terms have the following meanings unlessindicated otherwise:

alkyl--represents a straight or branched, saturated hydrocarbon chainhaving from 1 to 20 carbon atoms;

cycloalkyl--represents a saturated carbocyclic ring having from 3 to 6carbon atoms;

halogen (halo)--represents fluoro, chloro, bromo or iodo;

DMF--stands for (N,N-dimethylforamide);

LDA--stands for lithium diisopropylamide;

PDC--stands for pyridinium dichromate;

proton sponge--stands for 1,8-bis(dimethylamino)-naphthalene,N,N,N',N'-tetramethyl-1,8-naphthalenediamine!;

SEM--stands for 2-(trimethylsilyl)ethoxymethyl;

THF--stands for tetrahydrofuran; and

TMEDA--stands for N,N,N',N'-tetramethylethylenediamine.

Also, unless stated otherwise, the substituents for the variousembodiments described below are as defined for Formula 1.0.

Preferably, for compounds of Formula 1.0, m is 1; R⁵ is selected fromthe group consisting of H and C₁ to C₁₅ alkyl; and R¹ to R⁴ are eachindependently selected from the group consisting of: H, C₁ to C₆ alkyl,and --(CH₂)_(q) --R⁶ wherein R⁶ is phenyl. Most preferably, R⁵ isselected from the group consisting of H and C₁ to C₆ alkyl with H andmethyl being even more preferable; and R³ and R⁴ are each independentlyselected from the group consisting of: H and methyl.

Representative compounds of this invention include compounds of theformula: ##STR14##

Representative compounds of Formula 1.0 include compounds of theFormula: ##STR15##

Representative compounds of Formula 1.0 also include compounds of theFormula: ##STR16## wherein R¹ is selected from the group consisting of:H and C₁ to C₆ alkyl, with H or methyl being preferred, and R⁵ isselected from the group consisting of: H, C₁ to C₆ alkyl, --C(O)OR',--C(O)R⁷, --C(O)NR⁷ R⁸, and --(CH₂)_(q) --R⁶ wherein R⁶ is phenyl, withH or methyl being preferred

Representative compounds of Formula 1.0 further include: ##STR17##

Certain compounds of the invention may exist in different isomeric(e.g., enantiomers and diastereoisomers) forms. The inventioncontemplates all such isomers both in pure form and in admixture,including racemic mixtures. Enol forms are also included.

The compounds of Formula 1.0 can exist in unsolvated as well as solvatedforms, including hydrated forms, e.g., hemi-hydrate. In general, thesolvated forms, with pharmaceutically acceptable solvents such as water,ethanol and the like are equivalent to the unsolvated forms for purposesof the invention.

Certain compounds of the invention will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Certain basic compounds of the invention also form pharmaceuticallyacceptable salts, e.g., acid addition salts. For example, the nitrogenatoms may form salts with acids. Examples of suitable acids for saltformation are hydrochloric, sulfuric, phosphoric, acetic, citric,oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose in the art. The salts are prepared by contacting the free baseform with a sufficient amount of the desired acid to produce a salt inthe conventional manner. The free base forms may be regenerated bytreating the salt with a suitable dilute aqueous base solution such asdilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodiumbicarbonate. The free base forms differ from their respective salt formssomewhat in certain physical properties, such as solubility in polarsolvents, but the acid and base salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

The following processes may be employed to produce compounds of Formula1.0. Unless stated otherwise, reactions are conducted at an appropriatetemperature which allows the reaction to proceed at a reasonable rate tocompletion.

A PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 0 AND p is4 ##STR18##

In Step 1 of Scheme 1, piperidine is reacted with di-tert-butyldicarbonate ((tBOC)₂ O) in an organic solvent optionally in the presenceof an organic base. The reaction is conducted at a temperature of about0 to about 30° C. Preferably, methylene chloride is used as the organicsolvent, but other suitable organic solvents include DMF and the like.Triethylamine is used as the organic base. Other bases which can be usedinclude 4-dimethylaminopyridine and the like. In compound (1), the t-BOCgroup is chosen as an activating group on nitrogen which increases thekinetic acidity of the α-proton such that a lithio salt would resultupon treatment with a strong organic base (for example, Step 2). Otheractivating groups on nitrogen, known in the art that can also beemployed include nitroso, phosphoryl, hindered acyl, and formamidine.(See Aldrichimica Acta, Vol. 8, No. 3, 1985).

In Step 2 of Scheme 1, the anion of compound (1) is reacted withcompound (2) ##STR19## to produce compound (3). The reaction isconducted in an inert organic solvent containing an organic base andTMEDA (N,N,N',N'-tetramethylethylenediamine). The reaction is conductedat a temperature of about -78° to about 25° C. (room temperature).Tetrahydrofuran is preferably used as the solvent, other suitablesolvents include diethyl ether and the like. The anion of (1) isprepared by treatment of (1) with sec-butyl-lithium in THF at -78° C.

Z represents the protecting group ##STR20##

Z can be other protecting groups, such as2-(trimethylsilyl)ethoxymethyl, benzyloxycarbonyl and the like; however,unless stated otherwise, Z preferably represents the trityl group in theprocess described below for making the compounds of this invention.

Those skilled in the art will appreciate that other protecting groupsknown in the art may be used--such as, for example, base sensitivegroups wherein the protected compounds would be deprotected using basicconditions (e.g., NaOH). The processes described herein wherein theprotected compound is deprotected under acidic conditions may also becarried out under basic conditions when a base sensitive protectinggroup is used.

Compound (2) is prepared in two steps from compound (4): ##STR21##Compound (4) is reacted with an organometallic reagent R¹ M, wherein Mis Li or MgBr, to produce compound (5). The reaction takes place in aninert organic solvent at a temperature of about -78° C. to 0° C.Suitable inert organic solvents include: THF, diethyl ether and thelike. Compound (5) is then reacted with thionyl chloride in an inertorganic solvent, such as benzene or CH₂ Cl₂, in the presence of base togenerate compound (2). The reaction is conducted at a temperature ofabout -20° C. to 80° C. Suitable bases include: pyridine, triethylamine,and the like. Preferably, triethylamine is used as the amine base.Compound (4) can be obtained by following the literature procedure setforth in J. K Kelly, et al., J. Med. Chem., 20, 721 (1977).

In Step 3 of Scheme 1, compound (3) is treated with HCl or similar acidin an inert organic solvent such as ethyl acetate or dioxane, at atemperature of about 0° C. to selectively deprotect (3) thus producingcompound (6).

In Step 4 of Scheme 1, compound (6) may be reacted with (i) R⁵ --X (whenR⁵ is --C(O)R⁷, --C(O)OR^(7'), --C(O)NR⁷ R⁸ or alkyl) in an organicsolvent optionally in the presence of a suitable base (e.g.,triethylamine); or (ii) R^(5A) --CHO (when R⁵ is alkyl, cycloalkyl,allyl, propargyl, benzyl or substituted benzyl) in the presence of NaBH₃(CN) (sodium cyanoborohydride) or other hydrogenating conditions (e.g.H₂ /Pd/ROH) in an organic solvent; to produce compound (7). R^(5A)represents an R⁵ group that has one less --CH₂ -- group. Preferably, CH₂Cl₂ is used as the solvent when R⁵ --X is used, and tetrahydrofuran isused as the solvent when R^(5A) --CHO is used. X represents a suitableleaving group such as Cl, Br, I, or --OCH₃. The reaction ((i) or (ii))can be performed at a temperature within the range of about -30° toabout 80° C. Compound (7), when R⁵ is --C(O)NR⁷ H, may be prepared byreacting compound (6) with O═C═N--R⁷ in an organic solvent, such as CH₃CN or toluene. The reaction is performed at a temperature in the rangeof about 20 to reflux. Compound (6), or compound (7) wherein R⁵ is--C(O)O(t-butyl), can be reacted with aqueous acid (e.g., HCl, HBr, andthe like), at a temperature of about 25° to about 100° C., to producecompound (8) wherein R⁵ is H.

Compound (7), wherein R⁵ is --C(O)OR⁷, may be reacted with NHR⁷ R⁸ in anorganic solvent at a temperature of about 25° to about 100° C. to form acompound of (7) wherein R⁵ is --C(O)NR⁷ R⁸. The suitable organicsolvents include THF, toluene, DMF and the like.

In Step 5 of Scheme 1, compound (7) may be deprotected by treatment withdilute aqueous acid, such as HCl or HBr, at a temperature of about 70°to about 90° C. to produce compound (8). Other protecting groups areremoved by methods well known in the art.

Alternatively compound (3) of Preparation A can be prepared fromcompounds (1) and (4) according to Scheme 2: ##STR22##

In Step 1 of Scheme 2, compound (1)--see Step 1 of Scheme 1--is reachedwith compound (4) in accordance with the procedure set forth in Step 2of Scheme 1.

In Step 2 of Scheme 2, compound (9) is oxidized to produce compound(10). The oxidation is accomplished by treating compound (9) with anoxidizing agent, such as MnO₂ or PDC (pyridinium dichromate), in anorganic solvent, such as tetrahydrofuran or methylene chloride, at atemperature of about 20° to about 80° C.

In Step 3 of Scheme 2, compound (10) is reacted, under usual Wittigreaction conditions, with compound (11) ##STR23## in an organic solventat a temperature of about 25° to about 80° C. to produce compound (12).Preferably, the organic solvent is tetrahydrofuran; however, othersuitable solvents, such as 1,4-dioxane and the like, can be used. Incompound (11), R^(1A) represents an R¹ group which has one less --CH₂ --group.

In Step 4 of Scheme 2, compound (3) is produced when compound (12) ishydrogenated in THF with H₂ using a Pd-C (palladium/carbon) catalyst.Other organic solvents which can be used include ethyl acetate, methanoland the like. Other suitable metals such as Pt, Pd--Al₂ O₃, Ra--Ni, NiB,and Pd--CaCO₂ can also be employed as the hydrogenation catalyst.

In all the preparations that follow, intermediate compounds wherein theimidazole nitrogen is protected by Z and the nitrogen of the cyclic sixmembered amine is substituted with --C(O)O(t-butyl) or unsubstituted,i.e., hydrogen is bound to the amine nitrogen, such as in compounds (7)or (6), respectively, such intermediate compounds can be reacted withaqueous acid (e.g., HCl, HBr, and the like), at a temperature of about25° to about 100° C., to produce deprotected final products wherein R⁵is H, e.g., compound (8).

B. PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 1 AND p is 3 ##STR24##

In Step 1 of Scheme 3, α-valerolactam is reacted with R⁹ --L to placethe R⁹ on the indicated nitrogen atom in compound (13). R⁹ can either beSi(CH₃)₂ C(CH₃)₃ or other protecting group, or R⁹ can be an alkyl,cycloalkyl, benzyl, substituted benzyl, allyl, or propargyl group. Inthe latter, R⁹ is the same as R⁵. L is a leaving group, such as Cl, Br,I or --OSO₂ CF₃. The reaction is conducted in an organic solvent such asTHF, diethyl ether or 1,4-dioxane in the presence of a suitable base,such as lithium diisopropylamide (LDA), KH or NaH. The reaction takesplace at a temperature within the range of about -78° to about 80° C.

In Step 2 of Scheme 3, the anion of compound (13) is reacted withcompound (4) in an organic solvent, containing an organic base, at atemperature of about -78° to about 25° C. to produce compound (14).Suitable organic solvents include tetrahydrofuran and the like.Preferably, the organic base used to generate the anion of (13) islithium diisopropylamide or MN Si(CH₃)₃ !₂ wherein M is a metal cationsuch as Li, Na, or K Z is trityl or other suitable protecting group.

In Step 3 of Scheme 3, compound (14) is reacted with R¹ --Q, wherein Qis Li or MgBr, in tetrahydrofuran containing CuCN and a Lewis acid, suchas BF₃.(C₂ H₅)₂ O, (CH₃)₃ SiCl and the like, to produce compound (15).The reaction is conducted at a temperature of about -78° to about 20° C.Tetrahydrofuran is the preferred organic solvent; however, othersuitable solvents include diethyl ether and the like.

Compound (15) in Scheme 3 can alternatively be prepared by reacting ananion of compound (13) with compound (2) (see Step 2 of Scheme 1) in thepresence of an organic base. Inert organic solvents, such as THF,1,4-dioxane and the like can be employed. Preferably, the organic baseused to generate the anion of (13) is lithium diisopropylamide or MNSi(CH₃)₃ !₂ wherein M is a metal cation such as Li, Na, or K. Thereaction takes place at a temperature of about -78° C. to about 25° C.

In Step 4 of Scheme 3, the enolate of compound (15) is reacted with R⁴--L in an inert organic solvent to produce compound (16). The reactioncan be conducted at a temperature of about 0° to about 50° C. L is asuitable leaving group such as Cl, Br, I and the like. Preferably, KH isused as the base to form the enolate, but other suitable bases includeLDA and the like. Suitable organic solvents include THF, 1,4-dioxane andthe like. Preferably, THF is used.

In Step 5 of Scheme 3, compound (16) is reduced with LiAlH₄ at atemperature of about 0° to about 65° C. to produce compound (17). Thereduction is conducted in tetrahydrofuran, 1,4-dioxane and the like;however, THF is preferable. Other suitable reducing agents include BH₃(borane) and the like.

Step 6 of Scheme 3 (compound (17) to (19)), is followed when R⁹ is thedesired substituent on the nitrogen, such as alkyl, cycloalkyl, benzyl,substituted benzyl, allyl, or propargyl. Step 7 of Scheme 3 (compound(17) to (18)), is followed when R⁹ is --Si(CH₃)₂ C(CH₃)₃.

In Step 6 of Scheme 3, compound (17), when R⁹ is alkyl, cycloalkyl,benzyl, substituted benzyl, allyl or propargyl, is deprotected followingthe procedure in Step 5 of Scheme 1 to produce compound (19).Alternatively, in Step 7 of Scheme 3, compound (17) is treated withtetrabutylammonium fluoride in tetrahydrofuran at a temperature of about0° to about 50° C. to produce compound (18).

In Step 8 of Scheme 3, the procedures in Steps 4 and 5 of Scheme 1 arefollowed so that compound (18) is converted to compound (19).

C. PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 1 AND p is 3 ##STR25##

Compound (20) is reacted with R³ --M (wherein M is Li, ZnBr or MgBr) intetrahydrofuran containing BF₃.(C₂ H₅)₂ O and CuCN at a temperature ofabout -78° to about 20° C. to produce compound (21). Other suitablesolvents such as diethyl ether can be used. Compound (21) is thenconverted to compound (22) in accordance with the reaction steps setforth in Scheme 3.

D. PREPARATION OF COMPOUNDS WHEREIN m IS 1 n IS 2 AND p is 2 ##STR26##

In Step 1 of Scheme 5, compound (23), wherein R is CH₃ or CH₂ --C₆ H₅,is reacted with Mg in an inert organic solvent, such as THF, at atemperature of about 50° to about 70° C. to form the Grignard reagent.The Grignard reagent is then coupled with compound (2), in the presenceof CuI or CuCN, to produce compound (24). This coupling reaction isconducted at a temperature of about -78° to about 20° C. THF is thepreferable solvent; however, other solvents such as 1,4-dioxane anddiethyl ether can be used.

In Step 2 of Scheme 5, compound (24), wherein R is CH₃, is demethylatedto produce compound (25) by following the literature procedures setforth either in the J. Am. Chem. Soc., 110, 8256 (1988) or in the J.Org. Chem., 49, 2081 (1984). For example, the latter procedure compound(24) is reacted with CIC(O)OCHClCH₃ in 1,2-dichloroethane at about 0° toabout 85° C. in the presence of proton sponge to produce compound (25).Alternatively, compound (24), wherein R is CH₂ --C₆ H₅, is converted tocompound (25) under either the hydrogenation conditions ortransfer-hydrogenation conditions. For the former, the reaction isconducted in THF using Pd--C as catalyst, at a temperature of about 20°to about 70° C. Other organic solvents which can be used include ethanoland the like. Other suitable metals such as Pt, Pd--Al₂ O₃ and the likecan also be employed as catalysts. For the latter, the source ofhydrogen is ammonium formate (NH₄ COO), the catalyst is Pd/C, at atemperature of about 20° to about 80° C. The suitable organic solventsinclude methanol, ethanol and the like.

In Step 3 of Scheme 5, compound (25) is converted to compound (26) inaccordance with the procedure set forth in Step 4 and 5 of Scheme 1.

Compound (26), wherein R⁵ is CH₃ or CH₂ --C₆ H₅, can be directlyprepared from compound (24), by a simple deprotection of the Z group, byfollowing the procedure set forth in Step 5 of Scheme 1.

E PREPARATION OF COMPOUNDS WHEREIN m IS 1. n IS 2 AND p is 2 ##STR27##

In Step 1 of Scheme 6, compound (2) is reacted with a metal (M═Zn or Mg)in an inert organic solvent, such as THF and the like, at a temperatureof about -20° to about 60° C., to generate either an organozinc reagent(when M═Zn) or a Grignard reagent (when M═Mg). This organometallicreagent is then reacted with CuCN.2LiCl in THF to form an intermediate,compound (27), which is subsequently coupled with compound (20), in thepresence of BF₃.(C₂ H₅ O)₂ or (CH₃)₃ SiCl, to form compound (28). Thiscoupling reaction is conducted in an inert organic solvent, such as THF,1.4-dioxane or diethyl ether, at a temperature of about -78° to 50° C.

In Step 2 of Scheme 6, the anion of compound (28) is reacted with R³ --Xand then with R⁴ --X to produce compound (29). X represents a suitableleaving group, such as Cl, Br, I or --OSO₂ --CF₃. Each reaction to placeeach substituent group on the ring takes place in an organic solventusing an organic base. THF is the solvent usually used; however, othersuitable solvents include 1,4-dioxane, diethyl ether and the like.Examples of organic bases include lithium diisopropylamide, MN Si(CH₃)₃!₂, KH and like. M represents a suitable metal cation such as Na, Li, K,and the like. The reaction is usually conducted at a temperature ofabout -78° to about 80° C.

In Step 3, compound (29) is reduced to compound (30) in accordance withthe procedure set forth in Step 5 of Scheme 3.

In Step 4, the procedure in Step 6 or Steps 7 and 8 of Scheme 3 can befollowed so that compound (30) is converted to compound (31).

F. PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 2 AND p is 2 ##STR28##

In Step 1 of Scheme 7, 4-chloropiperidine is reacted with R⁹ --L toplace an R⁹ on the nitrogen atom of compound (32). Both R⁹ and L are asdefined above in Step 1 of Scheme 3. The reaction is conducted in anorganic solvent, such as THF, methylene chloride and the like, in thepresence of a suitable base, such as triethylamine or 4-dimethylaminopyridine. The reaction takes place at a temperature within the range ofabout 0° to about 70° C.

In Step 2 of Scheme 7, compound (32) is converted to compound (34) inaccordance with the reaction conditions set forth for the conversion ofcompound (23) to compound (24) (See Step 1 of Scheme 5).

In Step 3 of Scheme 7, compound (34) is chlorinated with sulfurylchloride to form compound (35). This reaction is conducted at atemperature of about 0° to about 50° C. in an inert organic solvent andin the presence of suitable base. Dichloromethane is the preferredsolvent, other solvents such as 1,2-dichloroethane can also be used.Suitable organic bases include triethylamine, 4-dimethylaminopyridineand the like.

In Step 4 of Scheme 7, the conversion of compound (35) to compound (36)is achieved in a two step sequence. First, compound (35) is reacted withformamide at about 175° C. (See Chem. Ber., Vol. 86, p. 88 (1953)) toform the imidazole ring. In the next step, the imidazole is protectedwith a Z group by reacting the product of the first step with Z-L in thepresence of an organic base to give compound (36). L is a leaving group,such as Cl or Br, and Z is as defined above in Step 2 of Scheme 1.Suitable organic solvents for the protection step include methylenechloride, dimethylformamide and the like. Suitable organic bases includetriethylamine and the like. The reaction may be performed at atemperature of about 0° to about 50° C.

In Step 5 of Scheme 7, compound (36) is converted to compound (26A) inaccordance with the sequence set forth in Step 6 or Steps 7 and 8 inScheme 3.

G. PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 2 AND p is2 ##STR29##

In Step 1 of Scheme 8, 4-halopyridine (wherein X is Cl, Br or I) isconverted to the corresponding organocuprate reagent (37) by reactionwith butyllithium and then with CuCN in an inert organic solvent at atemperature of about -78° to about 0° C. Suitable organic solventsinclude THF, diethylether and the like. The organocuprate (37) thusformed is then coupled with the α,β-unsaturated aldehyde (33) to formcompound (38). The coupling reaction is performed at a temperature of-78° C. to 20° C. in THF in accordance with the procedure set forth inStep 1 of Scheme 6.

In Step 2 of Scheme 8, compound (38) is reacted with sulfuryl chloride,in accordance with the procedure set forth in Step 3 of of Scheme 7, togive compound (39).

In Step 3 of Scheme 8, compound (39) is then converted to compound (40)using the Bredereck Reaction conditions (See Chem. Ber., 86, 88 (1954)).

In Step 4 of Scheme 8, compound (40) is hydrogenated to compound (41),under a hydrogen pressure of about 1 to about 100 atmospheres, in thepresence of suitable catalyst and in an acidic aqueous solvent. Suitablehydrogenation catalysts include Pd-black or Rh/C and the like. Suitablesolvents include 10% aqueous hydrochloric acid, or 10% aqueous sulfuricacid, or the like. The reaction takes place at a temperature of about20° to about 100° C.

In Step 5 of Scheme 8, compound (41) is converted to compound (26A) inaccordance with the procedure set forth in Step 4 of Scheme 1.

H. PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 1 AND p is 3 ##STR30##

By following the reaction sequence set forth in Scheme 8, compound (19A)is prepared by starting with the 3-halopyridine, wherein X is Cl, Br, orI.

I. PREPARATION OF COMPOUNDS WHEREIN m IS 1, n IS 0 AND p is 4 ##STR31##

2-Halopyridine, wherein X is Cl, Br or I, is converted to compound (8A)by following the sequence set forth in Scheme 8.

J. PREPARATION OF COMPOUNDS WHEREIN m IS 2, n IS 0 AND p IS 4: or m IS2, n IS 1 AND p IS3

By following the steps in Schemes 1 to 4 with the exception thatcompound (42) ##STR32## is used instead of compound (2) and compound(43) ##STR33## is used in place of compound (4), compounds (44), (45)and/or (47) ##STR34## are produced. Compound (44) is produced byfollowing Scheme 1 or Scheme 2, and compound (45) and (47) are producedby following Scheme 3 and Scheme 4, respectively. G represents asuitable leaving group such as Br, I, --OSO₂ --C₆ H₄ --CH₃, --OSO₂--CF₃, --OSO₂ --CH₃ and the like. The preparation of compound (42) isdescribed below. ##STR35## Compound (48) is produced by reactingcompound (46) (wherein Y is either CN or COOR¹⁰ wherein R¹⁰ is C₁ to C₅alkyl) in an organic solvent containing an organic base with R¹ --L andthen with R² --L in accordance with the method set forth in Step 2 ofScheme 6. Preferably, the organic solvent is tetrahydrofuran and theorganic base is lithium diisopropylamide. L is a suitable leaving groupsuch as Cl, Br, I, --OSO₂ --CF₃ and the like. Compound (48) is thenreduced to compound (49) in THF at a temperature of about -78° to about70° C. using diisobutylaluminum hydride (when Y is CN) orbis(2-methoxyethoxy)aluminum hydride (when Y is COOCH₃ ; see for exampleR. Kanazawa & T. Tokoroyama, Synthesis, 526 (1976)) as the reducingagent. Alternatively, the sequence of the preparation of compound (49)from (46) can be switched--i.e., reduction first and then introductionof R¹ and R².

Compound (49) is then reacted with either lithium aluminum hydride (whenR¹ is H) or R¹ --Q (when R¹ is not H) in tetrahydrofuran at atemperature of about -78° to about 0° C. to produce compound (50). Qrepresents Li or MgBr. When G represents a halide (i.e., Cl, Br, or I),then compound (42) is produced by either reacting compound (50) with (C₆H₅)₃ P/CG₄ or (C₆ H₅)₃ PG₃ (see Fiser & Fiser, Reagents for OrganicSynthesis, Vol. 1, p1247 (1967)). When G represents --OSO₂ --C₆ H₄--CH₃, --OSO₂ --CH₃ or --OSO₂ --CF₃, then compound (42) is produced byreacting compound (50) with Cl--SO₂ --C₆ H₄ --CH₃, Cl--SO₂ --CH₃ orCl--SO₂ --CF₃, respectively, in methylene chloride containingtriethylamine (as base) at a temperature of about -78° to about 0° C.

K PREPARATION OF COMPOUNDS WHEREIN m IS 2, n IS 2 AND p is 2

By following the steps in Scheme 5 and Scheme 6, with the exception thatcompound (42) (see Preparation J) is used instead of compound (2),compound (51) is produced following Scheme 5, and compound (52) isproduced following Scheme 6. ##STR36##

L PREPARATION OF COMPOUNDS WHEREIN DOUBLE BOND INDICATED IN FORMULA 1.0IS PRESENT AND WHEREIN m IS 1, n IS 2 AND p IS 2 ##STR37##

In Step 1 of Scheme 12, compound (32) is reacted with Mg, in accordancewith the procedure set forth in Step 1 of Scheme 5, to form thecorresponding Grignard reagent. This Grignard reagent is reacted withcompound (4) ##STR38## to form compound (53). The reaction takes placein a suitable organic solvent at a temperature of about -78° to about20° C. Suitable organic solvents include THF; 1,4-dioxane and the like.Preferably THF is used.

In Step 2 of Scheme 12, compound (53) is converted to compound (54),wherein R⁵ ' is H, alkyl, cycloalkyl, benzyl, substituted benzyl, allylor propargyl group, using an acidic aqueous solution, such as HCl, HBror the like. The conversion takes place at a temperature of about 50° toabout 100° C. Compound (54), wherein R^(5') is H, is then converted tocompound (55) in accordance with Step 4 of Scheme 1.

M. PREPARATION OF COMPOUNDS WHEREIN THE DOUBLE BOND IN FORMULA 1.0 ISPRESENT AND WHEREIN m IS 1, n IS 1 AND p IS 3 ##STR39##

In Step 1 of Scheme 13, compound (57) is produced when compound (56) isreacted with (t-BOC)₂ O and triethylamine. The reaction is conducted inan organic solvent, such as methylene chloride or DMF, using atemperature within the range of about 0° to about 250° C. (roomtemperature).

In Step 2 of Scheme 13, compound (58) is produced by treating compound(57) with an oxidizing agent such as pyridinium dichromate or similaroxidizing agent. The oxidation reaction is conducted in an organicsolvent, such as methylene chloride, using a temperature of about 25° toabout 50° C.

In Step 3 of Scheme 13, compound (59) is produced when the enolate ofcompound (58) is reacted with R³ --L wherein L is a suitable leavinggroup, such as halogen (e.g., Cl, Br, or I), --OSO₂ CF₃ and the like.The reaction takes place in an organic solvent, such as tetrahydrofuranor benzene, containing a suitable base, such as NaH, KH, LDA, orLiN(Si(CH₃)₃)₂. Preferably, tetrahydrofuran is used as the solvent andLDA is used as the base. The reaction is conducted at a temperature ofabout 0° to about 80° C.

In Step 4 of Scheme 13, the anion of compound (59) is reacted with R⁴--L using the same procedure set forth in Step 3 of Scheme 13 in orderto produce compound (60) and/or (61).

In Step 5 of Scheme 13, compound (63) or (63A) is obtained when compound(60) or (61) is reacted with compound (62) ##STR40## The reaction takesplace in an organic solvent, such as tetrahydrofuran, DMF or benzene,containing a suitable base, such as NaH, LDA, or LiN(Si(CH₃)₃)₂.Preferably, tetrahydrofuran is used as the solvent and LDA is used asthe base. The reaction is conducted at a temperature of about 0° toabout 80° C. Compound (62) is obtained by reacting compound (2A)##STR41## with P(C₆ H₅)₃ in an organic solvent, such as methylenechloride, CH₃ CN, tetrahydrofuran and the like, using a temperature ofabout 25° to about 50° C. In compounds (62) and (2A), Z representstrityl or SEM.

In Step 6 of Scheme 13, compound (64) and (64A) are prepared fromcompound (63) and (63A), respectively, by following the same procedureset forth in Steps 3 to 5 of Scheme 1.

In the steps of Scheme 13, alkylations (i.e., Steps 3 and 4) are only ifdesired and R³ and R⁴ are as defined for Formula 1.0.

N. PREPARATION OF COMPOUNDS WHEREIN THE DOUBLE BOND IN FORMULA 1.0 ISPRESENT AND WHEREIN m IS 1, n IS 2 AND p IS 2

By following the steps in Scheme 13, with the exception that compound(65) ##STR42## is used instead of compound (56), compound (66) and (66A)##STR43## are produced.

In the above processes, certain functional groups may be incompatablewith some transformations described herein, and consequently it issometimes desirable and/or necessary to protect certain groups duringthe reactions. Certain protecting groups are employed in the aboveprocesses but, as those skilled in the art will recognize, otherprotecting groups may be used in their place. Conventional protectinggroups are operable as described in Greene, T. W., and Wuts, P.G.M.,"Protective Groups In Organic Synthesis," John Wiley & Sons, New York,1991; the disclosure of which is incorporated herein by referencethereto. After the reaction or reactions, the protecting groups may beremoved by standard procedures.

The compounds of this invention are either agonists or antagonists ofthe histamine H₃ receptor. The binding affinity of the compounds of theinvention to the H₃ receptor may be demonstrated by the proceduredescribed below:

H₃ Receptor Binding Assay

The source of the H₃ receptors in this experiment was guinea pig brain.The animals used weighed 400-600 g. The tissue was homogenized using aPolytron in a solution of 50 mM Tris, pH 7.5. The final concentration oftissue in the homogenization buffer was 10% w/v. The homogenates werecentrifuged at 1000×g for 10 min. in order to remove clumps of tissueand debris. The resulting supernatants were then centrifuged at 50,000×gfor 20 min. in order to sediment the membranes, which were next washed 3times in homogenization buffer (50,000×g for 20 min. each). Themembranes were frozen and stored at -70° C. until needed.

All compounds to be tested were dissolved in DMSO and then diluted intothe binding buffer (50 mM Tris, pH 7.5) such that the finalconcentration was 2 μg/mL with 0.1% DMSO. Membranes were then added (400μg of protein) to the reaction tubes. The reaction was started by theaddition of 3 nM ³ H!R-α-methylhistamine (8.8 Ci/mmol) or ³H!-N-methylhistamine (80 Ci/mmol) and incubated at 30° for 30 min. Boundligand was separated from unbound ligand by filtration, and the amountof radioactive ligand bound to the membranes was quantitated by liquidscintillation spectrometry. All incubations were performed in duplicateand the standard error was less than 10% in all instances. Compoundsthat inhibited greater than 70% of the specific binding of radioactiveligand to the receptor were serially diluted to determine a K_(i) (μM).The results are given in Table 2.

In Table 2, the compound represented by (a*) is known in the art.

                  TABLE 2                                                         ______________________________________                                                                H.sub.3                                                                       Binding                                               COMPOUND                K.sub.i (μM)                                       ______________________________________                                         ##STR44##              0.014                                                  ##STR45##              0.19                                                   ##STR46##              0.0008                                                 ##STR47##              0.012                                                  ##STR48##              0.0003                                                ______________________________________                                    

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg to 500 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 1 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in one to four divided doses to achieverelief of the symptoms. The compounds are non-toxic when administeredwithin this dosage range.

The invention disclosed herein is exemplified by the followingpreparative examples, which should not be construed to limit the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

EXAMPLE 1 ##STR49##

To a solution of diisopropylamine (1.078 mL) in anhydrous THF (7 mL) wasadded n-butyllithium (3.08 mL; 2.5M) dropwise at 0° C.

The resulting solution was stirred at 0° C. for 40 minutes and then wascooled to -23° C. To this mixture was added N-methyl-2-piperidinone(0.80 mL) (1.) the mixture was stirred at -23° C. for 0.5 hour, and thenat -78° C. for 1 hour. To the above mixture was added dropwise asolution of 4-chloromethyl-N-trityl-imidazole (2.70 g) ##STR50## inanhydrous THF (14 mL). The mixture was stirred at -78° C. for 4 hoursand then was allowed to warm up to room temperature slowly overnight (16hours). Water and ethyl acetate were added to the mixture, the resultingmixture was shaken vigorously, the layers separated, and the aqueouslayer was extracted with ethyl acetate several times. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and evaporated to give the crude product, which waspurified by flash chromatography (1% to 2% of ammonia saturated methanolin CH₂ Cl₂) to give 2 (1.58 g; 52% yield). ##STR51##

To a solution of 2 (1.54 g) in anhydrous THF (8 mL) was added a 1Msolution of lithium aluminum hydride in diethyl ether (11 mL) at roomtemperature. The resulting solution was stirred for 2 hours and thendiethyl ether (100 mL) was added. To the above mixture was carefullyadded a saturated aqueous sodium sulfate solution until no more hydrogengas was evolved. The layers were separated, the aqueous layer wasbasified with K₂ CO₃ to pH 9 and then extracted with ethyl acetateseveral times. The combined organic layers were washed with brine, driedover anhydrous K₂ CO₃, and concentrated to give the crude product whichwas purified by flash chromatography (5% of ammonia saturated methanolin CH₂ Cl₂) to give a (1.27 g; 85% yield). ##STR52##

A solution of compound 3 (0.27 9) in a 0.5N HCl solution (20 mL) washeated to 90° C. for 30 minutes. After the mixture was cooled to roomtemperature, the mixture was extracted with diethyl ether four times.The aqueous layer was separated and concentrated under vacuum to yieldthe crude product which was recrystallized from CH₃ OH/diethyl ether togive 4 (0.141 g; 87% yield). MS (CI) 253 (M+1).

EXAMPLE 2 ##STR53##

To a solution of 7 g of compound 1 in 35 mL of distilled water at 0° C.was added 5 mL of a 50% aqueous NaOH solution. After 2 minutes ofstirring, the mixture was extracted with methylene chloride. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂ SO₄ and concentrated. The residue was distilled under vacuum (40°C./18 mmHg) to give 2.7 g of free amine 2 (50% yield). ##STR54## To amixture of magnesium turnings (0.73 g, 30.2 mmoles) in anhydrous THF (4mL) at 50° C. was added a solution of N-methyl-4-chloropiperidine 2 (2.7g, 20.2 mmoles) in 2 mL of anhydrous THF over the course of 1.5 hours.After the addition was complete, the resulting mixture was heated toreflux for 1.5 hours and then it was cooled to -55° C. Copper (I) iodide(0.192 g) was then added and the resulting mixture was stirred at -55° Cfor 3.5 hours. A solution of N-trityl-4-chloromethylimidazole (4.83 g)in 20 mL of THF was added. The resulting mixture was stirred to -₂₅° C.for 1 hour, at room temperature for 45 minutes, and then it was cooledat -20° C. Aqueous saturated NH₄ Cl solution was added to quench thereaction. The mixture was stirred at room temperature until the aqueouslayer turned a deep blue color. The organic layer was separated and theaqueous layer was extracted with ethyl acetate. The combined organicsolutions were washed with brine, dried over anhydrous Na₂ SO₄, filteredand concentrated. The residue was purified by flash chromatography(MeOH/EtOAc) to yield 2.26 g (40% yield) of compound 3. ##STR55##

A solution of compound 3 (1.55 g) in 40 mL of 0.5N aqueous hydrochloricacid was heated to reflux for 30 minutes. The mixture was cooled to roomtemperature and extracted with diethyl ether. The aqueous solution wasconcentrated and the residue was recrystallized from isopropanol/diethylether to give 0.6 g (65% yield) of compound 4. MS (CI) 180 (M+1).

EXAMPLE 3 ##STR56##

In a manner similar to that described in Example 2, Steps A and B.N-benzyl-4-chloropiperidine (1) is converted to compound 3. ##STR57##

To a solution of a (1.49 g) in 20 mL of anhydrous methanol was added0.95 g of ammonium formate (NH₄ COO), and 1.49 g of 10% Pd/C. Themixture was refluxed under nitrogen for 40 minutes, cooled to roomtemperature, and then filtered through a pad of celite. The filtrate wasconcentrated, and the residue was purified by flash chromatography onsilica gel to give 0.81 g (66% yield) of compound 4. ##STR58##

A solution of compound 4 (0.31 g ) in 25 mL of 1N aqueous hydrochloricacid was heated to reflux for one hour. The mixture was cooled to roomtemperature and extracted with diethyl ether. The aqueous solution wasconcentrated and the residue was recrystallized from isopropanol/diethylether to give 0.16 g (64% yield) of compound 5. MS (CI) 166 (M+1).

EXAMPLE 4 ##STR59##

To a mixture of magnesium turnings (0.73 g) in anhydrous THF (4mL) at50° C. was added a solution of N-methyl-4-chloropiperidine (2) (2.7 g)in 2 mL of anhydrous THF over the course of 1.5 hours. After theaddition was complete, the resulting mixture was heated to reflux for anadditional 1.5 hours and then the mixture was cooled to 0° C. A solutionof N-tritylimidazoylcarboxaldehyde (1) ##STR60## (6.83 g of 1 in 50 mLof THF) was added to the above Grignard reagent solution. The reactionmixture was stirred for 1 hour at 0° C. and then quenched with water.The organic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby flash chromatography on silica gel (eluting solvents: 1 to 10%ammonia saturated methanol in methylene chloride) to give 6.9 g (77% ofcompound 3). ##STR61##

A solution of 1.6 g of compound a in 40 mL of 85% sulfuric acid wasstirred at room temperature for 24 hours. After the solution was cooledto 0° C., the reaction mixture was basified with KOH to pH=9. Themixture was filtered and the filtrate was concentrated to approximately1/3 volume. The resulting solution was extracted with 2:1 ethylacetate/dichloromethane. The combined organic extracts were dried overanhydrous potassium carbonate, filtered, and concentrated to give an oilwhich was purified by preparative TLC (10% to 20% of ammonia saturatedmethanol in dichloromethane) to yield the free amine of 4. The freeamine of 4 was dissolved in dilute HCl and pumped dry to give 0.303 g(33%) of compound 4. MS (CI) 178 (M+1).

The following are examples of pharmaceutical dosage forms which containa compound of the invention. As used therein, the term "active compound"is used to designate the compound ##STR62##

The scope of the invention in its pharmaceutical composition aspect isnot to be limited by the examples provided, since any other compound ofstructural formula 1.0 can be substituted into the pharmaceuticalcomposition examples.

Pharmaceutical Dosage Form Examples

                  EXAMPLE A                                                       ______________________________________                                        Tablets                                                                       No.     Ingredients      mg/tablet                                                                              mg/tablet                                   ______________________________________                                        1.      Active compound  100      500                                         2.      Lactose USP      122      113                                         3.      Corn Starch, Food Grade,                                                                       30       40                                                  as a 10% paste in                                                             Purified Water                                                        4.      Corn Starch, Food Grade                                                                        45       40                                          5.      Magnesium Stearate                                                                             3        7                                                   Total            300      700                                         ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulatethe mixture with Item No. 3. Mill the damp granules through a coarsescreen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screenthe dried granules if necessary and mix with Item No. 4 and mix for10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

                  EXAMPLE B                                                       ______________________________________                                        Capsules                                                                      No.     Ingredients      mg/capsule                                                                              mg/capsule                                 ______________________________________                                        1.      Active compound  100       500                                        2.      Lactose USP      106       123                                        3.      Corn Starch, Food Grade                                                                        40        70                                         4.      Magnesium Stearate NF                                                                          4         7                                                  Total            250       700                                        ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of the formula: ##STR63## or apharmaceutically acceptable salt or solvate thereof, wherein: (A) m is1;(B) n and p are integers and are each independently selected from thegroup consisting of: 0, 1, 2, 3, and 4 such that the sum of n and p is 4and T is a 6-membered ring; (C) R³ and R⁴ are each independently boundto the same or different carbon atom of ring T such that there is onlyone R³ group and one R⁴ group in ring T, and each R¹, R², R³, and R⁴ isindependently selected from the group consisting of:(1) H; (2) C₁ to C₆alkyl; (D) R⁵ is selected from the group consisting of:(1) H; (2) C₁ toC₂₀ alkyl; (3) C₃ to C₆ cycloalkyl; (4) --C(O)OR^(7') ; wherein R^(7')is the same as R⁷ defined below except that R^(7') is not H; (5)--C(O)R⁷ ; (6) --C(O)NR⁷ R⁸ ; (7) allyl; (8) propargyl; and (9)--(CH₂)_(q) --R⁶, wherein q and R⁶ are as defined above, and when q isequal to 1, then R⁶ is not OH or SH; (E) R⁷ and R⁸ are eachindependently selected from the group consisting of: H, C₁ to C₆ alkyl,and C₃ to C₆ cycloalkyl; (F) the dotted line (------) represents adouble bond that is optionally present when m is 1, and n is not 0, andp is not 0, and when said double bond is present then R² is absent. 2.The compound of claim 1 wherein R⁵ is selected from the group consistingof H and C₁ to C₁₅ alkyl, and R¹ to R⁴ are each independently selectedfrom the group consisting of: H, C₁ to C₆ alkyl, and --(CH₂)_(q) --R⁶wherein R⁶ is phenyl.
 3. The compound of claim 2 wherein R⁵ is selectedfrom the group consisting of H and C₁ to C₆ alkyl, and R³ and R⁴ areeach independently selected from the group consisting of H and methyl.4. The compound of claim 3 wherein R⁵ is selected from the groupconsisting of H and methyl.
 5. The compound of claim 1 wherein saidcompound is selected from the group consisting of compounds having theformula: ##STR64## wherein R¹ to R⁵ are as defined for Formula 1.0. 6.The compound of claim 1 wherein said compound is selected from the groupconsisting of compounds having the formula: ##STR65## wherein R¹ to R⁵are as defined for Formula 1.0.
 7. The compound of claim 1 wherein R⁵ isselected from the group consisting of: H, C₁ to C₆ alkyl, --C(O)OR^(7'),--C(O)R⁷, --C(O)NR⁷ R⁸, and --(CH₂)_(q) --R⁶ wherein R⁶ is phenyl. 8.The compound of claim 7 wherein R² is H.
 9. The compound of claim 8wherein R⁵ is selected from the group consisting of H and C₁ to C₆alkyl, and R⁴ is H.
 10. The compound of claim l wherein said compound isselected from the group consisting of compounds having the formula:##STR66## wherein R¹ is selected from the group consisting of: H and C₁to C₆ alkyl, and R⁵ is selected from the group consisting of: H, C₁ toC₆ alkyl, --C(O)OR^('), --C(O)R⁷, --C(O)NR⁷ R⁸, and --(CH₂)_(q) R⁶wherein R⁶ is phenyl.
 11. The compound of claim 10 wherein R⁵ isselected from the group consisting of: H and C₁ to C₆ alkyl.
 12. Thecompound of claim 11 wherein R¹ and R⁵ are independently selected fromthe group consisting of: H and methyl.
 13. The compound of claim 1wherein said compound is selected from the group consisting of:##STR67##
 14. A compound of the formula: ##STR68##
 15. A compound of theformula: ##STR69##
 16. A pharmaceutical composition, comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a Compound of claim 1.